Single-Particle cryo-EM as a Pipeline
for Obtaining Atomic
Resolution Structures of Druggable
Targets in Preclinical Structure-Based
Drug Design
Ramanathan Natesh
Abstract Single-particle
cryo-electron
microscopy
(cryo-EM)
and
three-dimensional (3D) image processing have gained importance in the last few
years to obtain atomic structures of drug targets. Obtaining atomic-resolution 3D
structure better than *2.5 Å is a standard approach in pharma companies to design
and optimize therapeutic compounds against drug targets like proteins. Protein
crystallography is the main technique in solving the structures of drug targets at
atomic resolution. However, this technique requires protein crystals which in turn is
a major bottleneck. It was not possible to obtain the structure of proteins better than
2.5 Å resolution by any other methods apart from protein crystallography until
2015. Recent advances in single-particle cryo-EM and 3D image processing have
led to a resolution revolution in the field of structural biology that has led to
high-resolution protein structures, thus breaking the cryo-EM resolution barriers to
facilitate drug discovery. There are 24 structures solved by single-particle cryo-EM
with resolution 2.5 Å or better in the EMDataBank (EMDB) till date. Among
these, five cryo-EM 3D reconstructions of proteins in the EMDB have their associated coordinates deposited in Protein Data Bank (PDB), with bound inhibitor/
ligand. Thus, for the first time, single-particle cryo-EM was included in the
structure-based drug design (SBDD) pipeline for solving protein structures independently or where crystallography has failed to crystallize the protein. Further, this
technique can be complementary and supplementary to protein crystallography field
in solving 3D structures. Thus, single-particle cryo-EM can become a standard
approach in pharmaceutical industry in the design, validation, and optimization of
therapeutic compounds targeting therapeutically important protein molecules during preclinical drug discovery research. The present chapter will describe briefly the
history and the principles of single-particle cryo-EM and 3D image processing to
obtain atomic-resolution structure of proteins and their complex with their drug
targets/ligands.
R. Natesh (&)
School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram
(IISER-TVM), Maruthamala P.O.,Vithura, Trivandrum 695 551, Kerala, India
e-mail: natesh@iisertvm.ac.in
© Springer Nature Switzerland AG 2019
C. G. Mohan (ed.), Structural Bioinformatics: Applications in Preclinical Drug
Discovery Process, Challenges and Advances in Computational Chemistry
and Physics 27, https://doi.org/10.1007/978-3-030-05282-9_12
375
for Obtaining Atomic
Resolution Structures of Druggable
Targets in Preclinical Structure-Based
Drug Design
Ramanathan Natesh
Abstract Single-particle
cryo-electron
microscopy
(cryo-EM)
and
three-dimensional (3D) image processing have gained importance in the last few
years to obtain atomic structures of drug targets. Obtaining atomic-resolution 3D
structure better than *2.5 Å is a standard approach in pharma companies to design
and optimize therapeutic compounds against drug targets like proteins. Protein
crystallography is the main technique in solving the structures of drug targets at
atomic resolution. However, this technique requires protein crystals which in turn is
a major bottleneck. It was not possible to obtain the structure of proteins better than
2.5 Å resolution by any other methods apart from protein crystallography until
2015. Recent advances in single-particle cryo-EM and 3D image processing have
led to a resolution revolution in the field of structural biology that has led to
high-resolution protein structures, thus breaking the cryo-EM resolution barriers to
facilitate drug discovery. There are 24 structures solved by single-particle cryo-EM
with resolution 2.5 Å or better in the EMDataBank (EMDB) till date. Among
these, five cryo-EM 3D reconstructions of proteins in the EMDB have their associated coordinates deposited in Protein Data Bank (PDB), with bound inhibitor/
ligand. Thus, for the first time, single-particle cryo-EM was included in the
structure-based drug design (SBDD) pipeline for solving protein structures independently or where crystallography has failed to crystallize the protein. Further, this
technique can be complementary and supplementary to protein crystallography field
in solving 3D structures. Thus, single-particle cryo-EM can become a standard
approach in pharmaceutical industry in the design, validation, and optimization of
therapeutic compounds targeting therapeutically important protein molecules during preclinical drug discovery research. The present chapter will describe briefly the
history and the principles of single-particle cryo-EM and 3D image processing to
obtain atomic-resolution structure of proteins and their complex with their drug
targets/ligands.
R. Natesh (&)
School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram
(IISER-TVM), Maruthamala P.O.,Vithura, Trivandrum 695 551, Kerala, India
e-mail: natesh@iisertvm.ac.in
© Springer Nature Switzerland AG 2019
C. G. Mohan (ed.), Structural Bioinformatics: Applications in Preclinical Drug
Discovery Process, Challenges and Advances in Computational Chemistry
and Physics 27, https://doi.org/10.1007/978-3-030-05282-9_12
375